背景:JAK/STAT信号传导失调的先天性免疫错误(IEI)表现为免疫失调和感染的各种表现。造血干细胞移植(HSCT)是潜在的治愈,但最初报告的结果较差.JAK抑制剂(JAKi)提供了一种靶向治疗选择,可能是HSCT的替代或桥梁。然而,关于它们当前使用的数据,治疗效果和不良事件(AE)有限。
目的:我们评估了目前ESID/EBMT-IEWP中心中JAK/STATIEI的标签外JAKi治疗经验。
方法:多中心回顾性研究患有JAK/STAT信号过度活跃的遗传性疾病的患者,谁接受JAKI治疗至少3个月。
结果:评估了69例患者(72%的儿童)(45STAT1-GOF,21STAT3-GOF,1个STAT5B-GOF,1SOCS1-LOF,1JAK1-GOF)。鲁索替尼是主要的处方JAKI(80%)。总的来说,治疗使87%的STAT1-GOF患者和90%的STAT3-GOF患者的临床症状得到改善(部分或完全缓解).我们记录了非常不均匀的给药和监测方案。响应率和响应时间因不同疾病和表现而异。AE(即感染和体重增加)是常见的(38%的患者),但轻度(I-II级)和短暂的大多数患者。在最后的随访中,52/69(74%)的患者仍在接受JAKI治疗,而11例患者在之前的JAKI桥接治疗后最终接受了HSCT,总生存率为91%.
结论:我们的研究表明JAKi可能对有症状的JAK/STAT-IEI患者非常有效。应进行前瞻性研究,以确定可变临床表现和年龄范围的最佳JAKi剂量。
Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited.
We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers.
We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months.
Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival.
Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.